Therapeutic delivery device

ABSTRACT

A therapeutic delivery device that provides a controlled release of high doses of a therapeutic agent in a local area, sustains the high dose controlled release with a percutaneous port for refilling the device, and is versatile for use with multiple types of therapeutic agents and/or implant systems. A rate determining/controlled release membrane is used to decrease the molecular mobility of the therapeutic compounds thereby controlling the therapeutic release profile. The therapeutic delivery device includes a body defining an internal reservoir for receiving a therapeutic agent and including a first membrane for providing a controlled release of the therapeutic agent to the surgical site, a port in fluid communication with the reservoir, a sleeve configured to encapsulate the body, and a rigid housing configured to support the body and a portion of the sleeve, the rigid housing configured to release the body and the sleeve after the body and the sleeve are anchored position relative to the surgical site.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a non-provisional of and claims the benefit of U.S.Provisional Application No. 62/537,596, filed on Jul. 27, 2017, thecontents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

There are advantages to delivering therapeutic agents in local regionsinstead of systemic therapy applications, which deliver agents globallyand in a dilutive fashion to an entire system. These advantages mightinclude higher, local doses than those that could be achieved safely bysystemic delivery, minimized side effects in non-target tissues, use ofless agent over the life of delivery that may reduce cost and/ormorbidity and targeted delivery to a site of interest. Several therapiesof local delivery that might benefit from this strategy includeantimicrobial, analgesic, antiseptic, chemotherapeutic,anti-inflammatory, and/or anesthetic management.

As a specific example: patients who suffer from open fractures of theextremities are susceptible to high levels of bacterial contamination,specifically those that reside in biofilms. It has been estimated thatgreater than 99% of bacteria in natural ecosystems (e.g., soil, dirt,human skin, GI tract, etc.) preferentially dwell in the biofilmphenotype. Mud, dirty water, debris or other exogenous vectors thatharbor biofilms, or high numbers of planktonic bacteria, have potentialto contaminate open fracture wounds at the time of trauma and result inbiofilm-related infection. However, current antibiotic therapies, whichoften consist of short-term prophylactic administration, have not beenoptimized against biofilms. Indeed, every antibiotic on the market hasbeen optimized against planktonic bacteria. As such, current dosingtherapies may not reach sufficient blood levels to effectively eradicatebiofilms. Notably, the situation is not unique to open fractures alone.Patients who receive implantable devices including total jointprosthetics, vascular devices, pacemakers, fracture fixation devices, orwho undergo surgery in general are at risk of being contaminated withbacteria, including those in the biofilm phenotype.

Antimicrobial therapies that are currently in clinical use remainlimited in their ability to effectively treat and preventbiofilm-related infections, in particular those that accompany the useof implanted devices. Current antibiotic therapies, includingprophylactic antibiotic dosing administered systemically, may not reachsufficient levels to effectively eradicate biofilm bacteria, or,additionally, high inocula of planktonic bacteria. It is now well-knownthat bacteria in biofilms are resilient and can be up to 1,000 timesmore tolerant to antibiotics compared to their planktonic counterparts.As such, despite antibiotic intervention, biofilms may remain in acontaminated wound site and serve as a reservoir of infection.

There are many instances, including open fracture wounds, in whichdevices such as fracture fixation plates are implanted (eithertemporarily or permanently) into a patient. These implantable devicesare susceptible to infection. Device-related infections are difficult totreat with clinically available antimicrobial therapies. Thecharacteristic microbiology at the implant surface underlies the uniquepathology of device-related infections. Bacteria colonize the foreignsurface and evade the host immune system using several advantageousfactors including the secretion of a protective extracellular polymeric(EP) matrix that envelopes the bacteria. Because of changes in thebacterial phenotype, the surface-attached biofilm community may betolerant of antibiotics up to 1,000 times the concentration required toeradicate the metabolically active free-living planktonicforms—concentrations which are toxic to susceptible tissues like thecochlea, liver, and kidneys when delivered systemically. The implantsurface thus serves as a nidus for infection harboring a community ofbacteria, which adapt to the low level systemic antibiotic treatments inclinical practice.

High rates of and difficult to treat infections that are seen inclinical scenarios may be exacerbated by biofilms. For example, sinceGustilo et al. defined the Type IIIB open fracture in 1984 over 30 yearsago, infection rates (52%) of these fracture types have remained largelyunchanged. These high rates of infection have hindered surgical outcomesand healing in soldiers and civilian patients. There are at least twomain reasons proposed here as to why this unacceptably high rate ofinfection has continued. First, current therapies have not targetedbiofilms, or high inocula of planktonic bacteria. As mentioned, biofilmshave significant opportunity to contaminate open fractures or otherwound sites at the time of trauma and current antibiotic therapies mayprovide insufficient coverage. Second, and related to the first, currenttherapies do not maintain sufficiently high doses/concentrations ofantibiotic to prevent biofilm-related infection, in particular in anarea that is not highly vascularized.

These high energy traumatic wounds and infection outcomes arehighlighted in military-related healthcare. In current militaryconflicts, lower extremity injuries are highly common. Murray hasoutlined that a large percentage of lower extremity combat wounds arecomplicated by infection. In the military theater, rates of openfracture formation are much higher compared to the civilian population.For example, 26% of all injuries in soldiers have been reported to befractures. Of those, 82% were open with rates of infection that havereached as high as 60%. Additional data from Brook Army Medical Center(BAMC) has shown that 40% of injured soldiers (26% of which hadorthopaedic trauma) from January to June of 2006 received courses ofantibiotics. Furthermore, Johnson et al. have shown that in a group of25 soldiers who suffered Type IIIB open fractures of the tibia, 77% oftheir wounds had bacteria present. Taken together, these data indicatethat the proposed problem is common and adversely affects woundedwarriors, as well as civilian patients, and limits successful surgicaloutcomes.

Biofilm-related infection is of ever-growing concern across a broadspectrum of healthcare-related practices. Bacteria can eithercontaminate a wound or surgical site, then form into a biofilm, orwell-established biofilms can contaminate these sites at the time oftrauma, injury or during surgery. Furthermore, antibiotic resistance isa growing threat.

SUMMARY OF THE INVENTION

To address these growing concerns, a therapeutic agent (e.g.,antimicrobial) releasing pouch has been developed for use in conjunctionwith a variety of implantable devices, body locations, or can be used asa standalone product in wounds or surgical sites.

Preliminary in vitro tests have shown efficacy by eradicating bothbiofilm and planktonic bacteria in the presence of the antimicrobialreleasing pouch. For example, under flow conditions (fluid exchange rateof approximately 14%/hr) in brain heart infusion broth, the pouch(filled with 15 mL of PBS that contained 70 mg/mL fosfomycin, 25 mg/mLgentamicin and 2 mg/mL rifampin) was able to fully eradicate 10⁹ colonyforming units (CFU) of methicillin-resistant Staphylococcus aureus(MRSA) within a 24 hr period. In the presence of serum, the sameantibiotic combination in the pouch was able to reduce MRSA biofilms bymore than 6 log₁₀ units in 24 hr. In vivo testing in a sheep model ofType IIIB open fracture, wherein the pouch was placed sub-dermally yetdirectly over an implant site that contained 10⁹ CFU of MRSA inbiofilms, showed the ability of the pouch to treat and prevent biofilmimplant-related infection.

In one embodiment, the present invention provides a therapeutic deliverydevice that will provide the ability to release high doses of atherapeutic compound (e.g., an antibiotic) in a local area (importantfor effective biofilm eradication or eradication of high numbers ofplanktonic bacteria), sustain that high dose release with a percutaneousport that will allow for reloadability of the device, and be versatilefor use with multiple types of antimicrobials and/or implant systems. Arate determining/controlled release membrane is used to decrease themolecular mobility of the therapeutic compounds thereby controlling thetherapeutic release profile. Materials for this membrane might broadlyinclude nano- and micro-porous size exclusion membranes (e.g.,semi-permeable membranes, micromachined polymers or metals, etc.),hydrophilic polymer systems, or hydrogels.

In another embodiment, the present invention provides a therapeuticdelivery device that includes a body including a rate determiningmembrane. The body defines an internal reservoir and is configured to bedeployed subcutaneously. The device also includes a port having a cap.The port is in fluid communication with the reservoir and is configuredto extend percutaneously from the body to the surrounding environmentsuch that the cap is externally exposed thereby allowing a user torefill the reservoir via the port.

In one construction, the therapeutic delivery device may include anouter protective sleeve encasing the pouch to, for example, protect themembrane from punctures or bursting.

In another construction, the outer protective sleeve may be distinctfrom the membrane of the pouch or the outer protective sleeve may becombined with the membrane of the pouch (e.g., in a double-walled systemor composite membrane).

In a further construction, the outer protective sleeve may beconstructed from a fibrous material or fabric with a greater therapeuticpermeability than, for example, a rate determining membrane. The outersleeve may contain features to allow for attachment to tissue throughclinically available fasteners (e.g., sutures, staples, pins,unidirectional barbed sutures, etc.). The outer sleeve may includeradiopaque markers for positioning, locating, or adjusting withfluoroscopy or X-ray collection.

In yet another embodiment, the present invention provides a method fordeploying a therapeutic delivery device within a patient includinginserting the pouch into the patient such that a body of the pouch thatincludes a rate determining membrane at least partially defining thebounds of a reservoir is disposed subcutaneously within the patient. Inaddition, a port of the pouch that is fluidly coupled to the reservoirextends from the body percutaneously to the surrounding environment. Themethod also includes delivering a therapeutic agent contained with thereservoir to tissue and fluids of the patient surrounding the body viathe rate determining membrane. The method also includes refilling thereservoir with the therapeutic agent via the port in order to continuedelivering therapeutic agent. The method also includes removing thepouch from the patient after the reservoir has been substantiallyemptied.

In a further embodiment, the invention provides a therapeutic deliverydevice comprising a body defining an internal reservoir for atherapeutic agent and configured to be deployed subcutaneously near asurgical site, the body including a first membrane for controlledrelease of the therapeutic agent to the surgical site, a port includinga cap and a stem, the port in fluid communication with the reservoir andbeing configured such that the cap allows a user to refill the reservoirvia the port, and a sleeve configured to encapsulate the body, thesleeve including a tab region configured to receive a fastener to anchorthe body in position relative to the surgical site, the sleeve includinga second membrane to deliver the therapeutic agent from the body to thesurgical site.

In another embodiment, the invention provides a therapeutic deliverydevice comprising a body defining an internal reservoir for receiving atherapeutic agent and configured to be deployed subcutaneously near asurgical site, the body including a first membrane for providing acontrolled release of the therapeutic agent to the surgical site, a portin fluid communication with the reservoir, a sleeve configured toencapsulate the body, the sleeve including a tab region configured toreceive a fastener, the sleeve including a second membrane to deliverthe therapeutic agent from the body to the surgical site, and a rigidhousing configured to support the body and a portion of the sleeve, thetab region extending from a gap in the rigid housing, the rigid housingconfigured to release the body and the sleeve after the fastener toanchor the body and the sleeve in position relative to the surgicalsite.

In another embodiment, the invention provides a method for deploying atherapeutic delivery device within a patient, the therapeutic deliverydevice including a body, a port, and a sleeve. The method comprisesapplying a rigid housing over the therapeutic delivery device, insertingthe rigid housing into the patient through an incision and positioningthe body adjacent to a treatment site, anchoring the therapeuticdelivery device, releasing the rigid housing from the therapeuticdelivery device, removing the rigid housing through the incision,positioning the port for external access, filling the therapeuticdelivery device with a therapeutic agent via the port, delivering thetherapeutic agent in a controlled manner to the treatment site, andremoving the therapeutic delivery device from the patient.

Other features and aspects of the invention will become apparent byconsideration of the following detailed description and accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a therapeutic delivery device according to anembodiment of the present invention.

FIG. 2 illustrates the therapeutic delivery device of FIG. 1 beingfilled with a solution.

FIG. 3 is a schematic representation of the therapeutic delivery deviceof FIG. 1 disposed within a patient.

FIG. 4 is a set of images illustrating exemplary use of the therapeuticdelivery device.

FIG. 5A illustrates a therapeutic delivery device according to anembodiment of the present invention.

FIG. 5B illustrates the therapeutic delivery device of FIG. 5A disposedwithin sterilized packaging.

FIG. 5C illustrates the therapeutic delivery device of FIG. 5A that isfilled and coupled to a fluid source.

FIG. 6A illustrates a therapeutic delivery device according to anembodiment of the present invention.

FIG. 6B illustrates the therapeutic delivery device of FIG. 6A furtherincluding a protective sleeve.

FIG. 7 is a schematic representation of the therapeutic delivery deviceof FIGS. 6A and 6B disposed within a patient.

FIGS. 8A-C schematically illustrate a rigid housing for use with thetherapeutic delivery device illustrated in FIGS. 6A-B.

FIG. 9A illustrates the therapeutic delivery device of FIGS. 6A-Bincluding a drawstring and dual lumen port.

FIGS. 9B-C illustrate enlarged portions of a tab region of the sleeve ofFIG. 6B.

FIG. 9D illustrates an enlarged view of a pull tab and dual lumen port.

FIG. 9E illustrates the therapeutic delivery device of FIGS. 6A-Bincluding a drawstring and dual lumen port.

FIG. 9F illustrates the drawstring and pull tab.

FIG. 10A is a photograph of a first portion of a testing apparatus.

FIG. 10B is a photograph of a second portion of a testing apparatus.

FIG. 11A is a photograph of a set of testing objects.

FIG. 11B is a photograph of another set of testing objects.

FIGS. 12A-C is a set of photographs illustrating exemplary use of thetherapeutic delivery device of FIG. 6A.

FIG. 13 is a set of photographs illustrating exemplary extraction of thetherapeutic delivery device from a test subject.

FIGS. 14A-B are graphs illustrating release profiles of an exemplaryembodiment of the therapeutic delivery device.

FIG. 15 graphically illustrates improved release profiles of anexemplary embodiment of the therapeutic delivery device compared toclinical standards.

FIG. 16 shows another embodiment of a therapeutic delivery device.

Before any embodiments of the invention are explained in detail, it isto be understood that the invention is not limited in its application tothe details of construction and the arrangement of components set forthin the following description or illustrated in the following drawings.The invention is capable of other embodiments and of being practiced orof being carried out in various ways. Also, it is to be understood thatthe phraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting.

DETAILED DESCRIPTION

The terms rate determining membrane and control release membrane broadlydescribe membranes which can be used with embodiments of the invention,rather than a more narrow term “semi-permeable membrane”. Nearly allmembranes fit broadly into one of two classes: Size exclusion membranesand affinity membranes. Size exclusion membranes are semi-permeablemembranes which use physical pores to selectively pass solutes. Theseinclude: ultrafiltration membranes, microfiltration membranes,nanofiltration membranes, and dialysis membranes. Affinity membranes, onthe other hand, use molecular affinity interactions between the soluteand the membrane components or functional groups to slow down the solutediffusion rate within the membrane. Affinity membranes are much lesscommon but include hydrogels, polymer systems, and functionalizedpolymer systems. If selected carefully any number of these membranes ormembrane types might be used in the pouch to achieve the targettherapeutic delivery profile.

FIGS. 1-4 illustrate a therapeutic delivery device (e.g., pouch) 10configured to provide a therapeutic agents (e.g., antibiotics,antimicrobials, anti-tumor agents, steroids, analgesics,anti-inflammatories, etc.) to a wound site, surgical site or bodycavity. In one embodiment, the therapeutic delivery device 10 isconfigured as an antimicrobial pouch that is placed within awound/surgical site to deliver an antimicrobial agent within thewound/surgical site to prevent infections. Examples of suchwounds/surgical sites include implants/implant sites, abscesses,chronically infected wounds, and other localized infections. In oneexample, the therapeutic delivery device 10 may be placed within awound/surgical site after an open fracture of a bone within one of apatient's extremities (e.g., reduced with a fixation plate) to providehigh doses of antimicrobial agents over an extended period of time toprevent and treat biofilm infection.

With reference to FIG. 1, the therapeutic delivery device 10 includes abody 15 having an outer wall 20 that defines a reservoir 25 within thebody 15. The device 10 includes a port 30 coupled to the body 15. Theport 30 includes a stem 35 and an injection cap 40. The stem 35 extendsbetween the body 15 and the injection cap 40. The port 30 is in fluidcommunication with the reservoir 25 such that a liquid antimicrobialagent may be introduced into the reservoir 25 via the injection cap 40.In the illustrated embodiment, the injection cap 40 is configured toseal the reservoir 25 from outside contaminants, but receive the needleof a syringe 45 such that the reservoir 25 may be refilled orreplenished (FIG. 2). The injection cap 40 is constructed of aself-sealing material such that any aperture created by inserting thesyringe is automatically sealed when the syringe is withdrawn. However,in other embodiments, the injection cap 40 may be a needleless injectioncap 40 such that materials may be introduced using a needlelessinjection method without exposing the reservoir 25 to contaminants.

With continued reference to FIG. 1, the outer wall 20 of the body 15 isconstructed from at least one membrane 50 (such as, a rate determiningor control release membrane, for example, a nano and micro porous sizeexclusion membranes such as semi-permeable membranes or micromachinedpolymers or metals, affinity membranes such as hydrogels, polymersystems, and functionalized polymer systems, etc.) such that thereservoir 25 selectively communicates antimicrobial agents with thesurrounding environment. That is, the membrane 50 facilitates acontrolled release of the antimicrobial agents. In one construction, themembrane can comprise ethylene vinyl acetate or a polyurethane film suchas Medifilm® from Mylan.

In the illustrated embodiment, the body 15 has an end of the outer wall20 that is opposite the port 30 heat sealed to at least partiallyenclose the reservoir 25. However, other methods of sealing the body 15in order to form an internal reservoir 25 may be utilized. In anexemplary embodiment, the membrane 50 is a semi-permeable size exclusionmembrane with a molecular cut off of approximately 0.1-0.5 kDaltons(e.g., based on the molecular weights of cefepime, levofloxacin,fosfomycin, gentamicin, or rifampin). However, this embodiment is merelyexemplary and the molecular weight cut off of the semi-permeablemembrane 50 may be selected/customized in order to function with othertherapeutic agents. For example, membranes in the nano- andultra-filtration ranges with pore sizes from approximately 1-100 nm andmolecular cutoffs from 1-14 kDa may be used. The semi-permeable membrane50, in this example, is configured to enable delivery of theantimicrobial/therapeutic agent to the surrounding tissue according toan elution profile as defined by characteristics of the semi-permeablemembrane 50. For example, the semi-permeable membrane 50 may beconfigured to regulate molecular mobility and slow down the diffusion ofthe liquid antimicrobial agent through the semi-permeable membrane 50.In other examples, the membrane 50 may create a steady-state elutionprofile or a variable rate elution profile, among others. In any case,the elution profile is set such that a high concentration of theantimicrobial agent is maintained within the surgical site for apredetermined amount of time to prevent local infection. In addition,the device 10 can be modular such that rate of release (based onmembrane or other material selection) can be rapid, given as a bolusdose, which may be beneficial to eradicate biofilms quickly, orthrottled to deliver lower doses over a longer period of time, which maybe of interest for an alternate indication such as pain management.Other factors that may be utilized to control elution profiles includethe density of pores on the semi-permeable membrane 50 and the thicknessof the semi-permeable membrane 50.

In the illustrated embodiment, the stem 35 is a non-permeable tubeinterconnecting the injection cap 40 and the body 15. As such, thetherapeutic agent is delivered from the injection cap 40 to the body 15through the tube. In other embodiments, however, the stem 35 may be atleast partially constructed from a membrane (e.g., a similar membrane asdescribed above) such that the therapeutic agent is delivered to agreater volume within the wound site. For example, in thisconfiguration, the therapeutic agent would further be delivered directlyto the areas surrounding the percutaneous incision to prevent surgicalsite infection.

In other constructions, the stem 35 may be variable based on theapplication. For example, the length of the stem may be varied, the typeof connection may be varied (e.g., needled or needleless connection),and/or can be made of various materials (e.g., permeable ornon-permeable materials). In addition, the device 10 may includemultiple stems 35 to, for example, facilitate the introduction ofdifferent therapeutic agents or to form an inlet to fill the reservoirand a separate outlet to empty the reservoir.

In another construction, the port 30 and, more specifically, the stem35, may extend through the reservoir 25 of the body 15 to providestructural support to the body 15, aid in maintaining a more uniformbody profile (e.g., when the reservoir is empty), and to facilitate moreeven filling of the reservoir 25. In this embodiment, at least a portionof the stem 35 (e.g., the portion lying within the reservoir 25)includes apertures, perforations, permeable membrane portions, or othermeans for fluid communication between the stem 35 and the reservoir 25.

The therapeutic delivery device 10 may vary in size. In one example, thebody 15 is approximately 10 cm long. However, all aspects of the device10 may be tailored for specific uses and specific placements within theanatomy. For example, the size of the body 15 or the length of the stem35 may be varied (e.g., made longer so the device 10 may be placeddeeper into tissue). In addition, an introducer device may be used toaid in deployment of the device 10 in applications when a separatesurgery is not being performed (e.g., in the case of treatment asopposed to prophylaxis) such as treatment of osteomyelitis or infectionsassociated with previously implanted devices.

The therapeutic delivery device 10 has been tested for efficacy intreating biofilms. In one test, the device 10 was filled with anantibiotic solution and placed in test tubes that contained either 10⁸colony forming units (CFU)/mL or well-established biofilms ofmethicillin-resistant Staphylococcus aureus (MRSA). Fresh bacteria andsolution were added to the test tubes daily for 10 days and quantifiedeach day. With n=6 repeats, it was shown that planktonic and biofilmbacteria were eradicated completely.

With reference to FIGS. 14A-B, the elution profile of an exemplary 12-14kDa molecular weight cutoff semi-permeable membrane 50 was also testedand determined using an established flow cell system. The therapeuticdelivery device 10 was filled with 15 mL of antibiotic solution (acombination of fosfomycin, gentamicin and rifampin) with varyingconcentrations, and placed into a chamber of a flow cell unit thatcontained 50 mL of phosphate-buffered saline (PBS). PBS was flowedthrough the flow cell unit (turnover rate of approximately 14%/hr) tocreate a dynamic environment. Samples of eluate were collected every 2hrs for 24 hrs and it was shown that concentrations of rifampinincreased and decreased over the 24 hr period as hypothesized.

With reference to FIG. 15, additional release profiles were determinedwith gentamicin over a period of 10 days. Samples of eluate werecollected every 24 hrs. In one instance, the device was reloaded withfresh antibiotic every 24 hrs (black line). In another instance, thedevice was loaded a single time (green line). Release profiles werecompared to clinical standards of care that offer local, high doserelease, but cannot be reloaded (red, orange, turquoise and purplelines).

FIG. 3 illustrates a schematic representation of the therapeuticdelivery device 10 deployed within a fracture site in which thepatient's fracture has been reduced and fixated using a fixation plate.This type of wound site and the fracture plates are susceptible toinfection, particularly from infectious biofilms (e.g., non-planktonicbacteria such as MRSA). In order to provide a strong therapeutic effect,the body 15 of the device 10 is positioned entirely within the patient(i.e., beneath the skin) to deliver the therapeutic agent containedwithin the reservoir 25 to the wound site. Such a configuration enablesa high concentration of therapeutic agents to be delivered andmaintained locally in order to treat or prevent infection. In thisconfiguration, the stem 35 of the port 30 extends through an incision(i.e., extends percutaneously) to expose the injection cap 40 to thesurrounding environment, thereby granting a user (e.g., the patient, anaide, a medical practitioner, etc.) access to the injection cap 40. Thisallows the user to refill the reservoir 25 as desired or instructed toenable long-term therapeutic agent delivery (e.g., hours, days, weeks,etc.) to continue to treat and prevent infection.

FIG. 4 illustrates deployment and use of the exemplary therapeuticdelivery device 10 within a test subject. As seen in image A of FIG. 4,the first step includes creating an incision to deploy the therapeuticdelivery device 10 within the subject. In other embodiments, however, apreviously made incision (e.g., a surgical incision or would site) maybe utilized. In a subsequent step, image B, the body 15 of the device 10is inserted subcutaneously within the subject, with the stem 35 of theport 30 extending percutaneously to expose the injection cap 40 to theenvironment. In this image, the reservoir 25 of the device 10 may beempty in order to reduce the size of the incision necessary to deploythe device 10, or the reservoir 25 may be at least partially filled whenthe device 10 is deployed. In the next image C, a suture line is used toclose the tissue surrounding the body 15 and the stem 35 of the port 30.In a subsequent step (image D), the reservoir 25 is filled using asyringe to deliver therapeutic agent to the reservoir 25 via theself-sealing injection cap 40 after at least a portion of thetherapeutic agent has been delivered to the wound site. It should benoted that this step may be repeated as necessary during the duration ofdeployment of the device 10. In a final step, illustrated in image E,the device 10 is removed from the patient. In this step, the device 10may be emptied (e.g., via full depletion of the reservoir 25 duringdeployment or by withdrawing remaining therapeutic agent via theinjection cap 40 with a syringe) to reduce the volume/cross-sectionalarea of the body 15. This enables removal via the incision, which may besubstantially smaller due to healing, with limited difficulty. In somecases, it may be necessary to remove one or more sutures in order toremove the device 10, but the size of the incision necessary for removalremains relatively small.

FIGS. 5A-C illustrates a therapeutic delivery device 110 according toanother embodiment of the present invention. The device 110 issubstantially similar to the device 10 described above. The features ofthe device 110 that are substantially the same as the features of thedevice 10 are indicated by the same reference numerals plus “100.” Thefollowing description focuses primarily on the differences between thedevice 110 and the device 10. However, it should be noted that featuresfrom the device 110 may be used on the device 10 and vice versa.

The therapeutic delivery device 110 includes a body 115 having an outerwall 120 that defines a reservoir 125 within the body 115. A port 130 iscoupled to the body 115 and includes a stem 135 extending between thebody 115 and an injection cap 140. The body 115 includes a ratedetermining membrane 150 having a molecular weight cut off of 12-14 kDa(e.g., a cellulose membrane). In this embodiment, the outer wall 120 issealed using a flexible medical grade adhesive (e.g., flexible medicalgrade cyanoacrylate Loctite ® 4902). The device 110 further includesholes 160 disposed in corners of the body 115 (e.g., on seams of thebody 115) for receiving sutures to anchor the device 10 in position.FIG. 5B illustrates placement of the antimicrobial pouch 110 within aTyvek® peel-pouch 180 to demonstrate sterilization feasibility viaethylene oxide. FIG. 5C illustrates a syringe coupled to the injectioncap 140 and filling the body 115 with a therapeutic agent as the body115 is shown in an expanded or filled state.

FIGS. 6A-B and 7 illustrate a therapeutic delivery device 210 accordingto another embodiment of the present invention. The device 210 issubstantially similar to the devices 10, 110 described above. Thefeatures of the device 210 that are substantially the same as thefeatures of the devices 10, 110 are indicated by the same referencenumerals as device 10 plus “200.” The follow description focusesprimarily on the differences between the device 210 and the devices 10,110. However, it should be noted that features from the device 210 maybe used on the devices 10, 110 and vice versa.

The device 210 includes a body 215 having an outer wall 220 that definesa reservoir 225 within the body 215. A port 230 is coupled to the body215 and includes a stem 235 extending between the body 215 and aninjection cap 240. In one construction, the injection cap 240 is aneedle-free injection valve (e.g., a SmartSite™ needle-free injectionvalve). The body 215 is closed using nylon material, and the stem 235 issecured to the body 215 using the same nylon material.

The device 210 also includes a sleeve 265 encapsulating the body 215 andat least a portion of the port 230 (e.g., a portion of the stem 235). Inone construction, the sleeve 265 is constructed from a highly porouspolymer material or a fibrous material like a fabric weave, braid, kit,or felt (e.g., such that the release rate of the sleeve is greater thanthe release rate of the membrane 250) and may include holes 270 (e.g.,as a site for attaching mechanical anchors such as sutures,unidirectional barbed sutures, staples, pins, etc. that mechanicallycouple the device 210 to a particular location in the patient) disposedon, for example, tabs 267 of the sleeve 265. The tabs 267 provide aboundary or extension in certain areas of the sleeve 265. In theillustrated embodiment, the tabs 267 are positioned at opposite ends ofthe sleeve 265, however it is noted that the tabs 267 may be positionedas needed depending on application and implantation techniques used. Inalternate embodiments, the sleeve 265 may include other permeable orsemi-permeable materials, such as a porous material thatprevents/discourages tissue ingrowth (e.g., ADAPTIC TOUCH™), may be usedin place of or in addition to the nylon plain weave fabric such that therate of release or elution profile of the therapeutic agent is furthereffected by the sleeve 265. In another alternate embodiment, the sleeve265 and the membrane 250 may be fused together (i.e., the sleeve 265 andthe membrane 250 form a composite membrane such as a thin film compositemembrane). Such an embodiment may also include additional sleeves 265and/or membranes forming additional layers in the composite membrane.

The sleeve 265 can be configured in the same way as the membrane 50described above to effect or control the release of the therapeuticagent. Furthermore, the sleeve 265 protects the membrane 250 fromcontact with abrasive objects that might cause a puncture such as jaggedbone, surgical instruments, fixation hardware, or bone cement, amongothers. In addition, the sleeve 265 protects the body 215 from burstingunder loads (e.g., overfilling, application of pressure to body 215,etc.). In some embodiments, the sleeve 265 includes radiopaque markersfor positioning, locating, or adjusting the device 210 within thepatient via fluoroscopy (e.g., C-arm imaging) or X-ray collection.

In this embodiment, the device 210 includes a removable rigid housing275 as illustrated in FIGS. 8A-C. The rigid housing 275 is configured toreceive the body 215 and provides protection to the body 215 and sleeve265 from puncture or damage during implantation. The housing 275includes an upper portion 280 and a lower portion 285 coupled to theupper portion 280. The lower portion 285 is divided into a first portion290 and a second portion 295. As illustrated, the upper portion 280 andthe lower portion 285 are hingedly coupled, and more particularly, thefirst portion 290 is hingedly coupled to the upper portion 280 at afirst side of the housing 275, and the second portion 295 is hingedlycoupled to the upper portion 280 at a second side of the housing 275opposite the first side. This configuration allows the first portion 290and the second portion 295 to separate (i.e., open) upon removal of thehousing 275.

With reference to FIGS. 8A-B, the rigid housing 275 provides a slightgap 300 between the upper portion 280 and the lower portion 285. The gap300 allows the tabs 267 on the sleeve 265 to extend from the housing275. As noted above, the tabs 267 include holes 270 which are used toanchor the sleeve 265 in position by suturing or other mechanicalfasteners without risk of needle damage to the device 210. Once thesurgical site is ready for closure, the housing 275 can be removed anddiscarded (FIG. 8C). In other constructions, the rigid housing 275 maybe configured as a single piece or multi-part with alternative couplingmechanisms. The housing 275 may include lettering directing cliniciansfor its removal before surgical site closure.

With reference to FIGS. 9A-F, the sleeve 265 may be modified to includeslits or holes 309 in the tabs 267 at each of the holes 270 (FIGS.9B-C). In this configuration, a drawstring 305 (FIGS. 9B & 9F) encirclesthe sleeve 265 to facilitate removal of the device 210. To accommodatethis construction, the stem 235 has a double lumen 311 where one lumenis used for filling, refilling, and deflating the body 215, and thesecond lumen supports the drawstring 305. The drawstring 305 includes apull tab 307 (FIG. 9D) at its proximal end and remains exterior of theuser.

During removal of the device 210, a pulling action on the pull tab 307(and thus the drawstring 305) untethers the device from the sutures,e.g., biodegradable (which will remain behind), used to secure thedevice 210 in position. This drawstring configuration allows the device210 to be removed less invasively by drawing it through the port andthus the small existing percutaneous hole in the tissue.

The therapeutic delivery device 210 was tested, in triplicate, againstwell-established MRSA biofilms grown on polyether ether ketone (PEEK)membranes in a modified CDC biofilm reactor. The biofilms were robustand contained 7.07±2.42×10⁷CFU/membrane. The devices were loaded with 15mL of a triple-antibiotic solution in PBS: 2 mg/ml rifampin, 25 mg/mLgentamycin, and 75 mg/ml fosfomycin. The devices and biofilm membraneswere submerged in 30 mL of 10% BHI and incubated at 37° C. The biofilmswere completely eradicated for all three devices tested within 24 hours.

This in vitro model was then expanded to account for lymphatic flow,which will inevitably clear antibiotics from living tissues, as would bethe case if the device were used as intended and implanted in anoperation site. The model setup is illustrated in FIGS. 10A-B. Briefly,the devices were loaded with a 15 ml solution of triple-antibiotic andeach submerged in 50 ml of 10% BHI in a flow chamber (FIG. 10B).Similarly, MRSA biofilms at 6.60±2.95×10⁸ CFU/membrane (FIG. 11A), wereplaced in each flow chamber. A fresh solution of 10% BHI was continuallypumped through each cell with an exchange rate of 16% per hour to mimicthe clearance rate in human tissues. Within 24 hours, the associatedbiofilms were completely eradicated for all 5 devices tested (FIG. 11B).

Referring to FIG. 12, a procedure was performed with the therapeuticdelivery device 210 in a sheep carcass. In this procedure, an incisionwas made in the proximal medial aspect of the sheep tibia. Afterplacement of the orthopedic implants (image A) the inflated/filleddevice 210 (image B) was anchored to the skin with a suture in eachcorner (e.g., via the holes 270), thereby ensuring the device 210 satfirmly just above the implant. Then the wound was closed (image C). Abulbous protrusion was created by the inflated percutaneous device 210.The device 210 was easily extracted by cutting the four anchoringsutures, deflating the device 210, and gently sliding it out through thesmall percutaneous port hole (FIG. 13).

There are multiple benefits associated with the therapeutic deliverydevice 10. For example, the device 10 can provide local, high doserelease of therapeutic agents into the surrounding tissue and fluid of apatient—an important requirement to treat and prevent infection (e.g.,biofilm device-related infection, etc.). Another exemplary benefit ofthe device 10 is the ability to sustain that high dose release oftherapeutic agent via the reloadable or refillable design, which mayreduce the risk of resistance development. A final exemplary benefitwould be the versatility of the device 10. For example, the device 10has the ability to be loaded with a variety of therapeutic agents otherthan antimicrobials, including traditional antibiotics,nanotechnologies, or novel antimicrobials that are under development.

FIG. 16 illustrates a therapeutic delivery device 310 according toanother embodiment of the present invention. The device 310 issubstantially similar to the devices 10, 110, 210 described above. Thefeatures of the device 310 that are substantially the same as thefeatures of the devices 10, 110, 210 are indicated by the same referencenumerals as device 10 plus “300.” The follow description will focusprimarily on the differences between the device 310 and the devices 10,110, 210. However, it should be noted that features from the device 310may be used on the devices 10, 110, 210 and vice versa.

The therapeutic delivery device 310 includes a subcutaneous port 332coupled to the body 315. In this embodiment, the subcutaneous port 332is placed into the patient beneath subcutaneous tissue and may beaccessed, for example, using a needle. This configuration allows for arefilling system in which no portion of the pouch 310 extendspercutaneously. This may, for example, reduce the risk of infectionproximate the port.

Although the invention has been described in detail with reference tocertain preferred embodiments, variations and modifications exist withinthe scope and spirit of one or more independent aspects of the inventionas described.

What is claimed is:
 1. A therapeutic delivery device comprising: a bodydefining an internal reservoir for a therapeutic agent and configured tobe deployed subcutaneously near a surgical site, the body including afirst membrane for controlled release of the therapeutic agent to thesurgical site; a port including a stem, the port in fluid communicationwith the reservoir and being configured such that a user can refill thereservoir via the port; and a sleeve configured to encapsulate the body,the sleeve including a tab region configured to receive one or morefastener to anchor the body in position relative to the surgical site,the sleeve including a second membrane to deliver the therapeutic agentfrom the body to the surgical site; a drawstring encircling the sleeve;wherein the stem has a dual lumen, wherein a first lumen is incommunication with the reservoir and a second lumen receives thedrawstring that extends percutaneously from the body to the surroundingenvironment.
 2. The therapeutic delivery device according to claim 1,wherein the access point of the port is needleless.
 3. The therapeuticdelivery device according to claim 1, wherein the port is configured toextend percutaneously from the body to the surrounding environment. 4.The therapeutic delivery device according to claim 1, wherein the portis configured to be deployed subdermally such that a user can refill thereservoir via the port.
 5. The therapeutic delivery device according toclaim 1, wherein the first membrane comprises a polyurethane film. 6.The therapeutic delivery device according to claim 1, wherein the tabregion includes a hole or a slit and a drawstring that is pulled throughall the holes or the slits of the sleeve allowing the therapeutic deviceto be untethered from the one or more fasteners thereby allowing thetherapeutic device to be removed from the surgical site.